How are Alzheimer's disease and type II diabetes related?
Special April Issue of the Journal of Alzheimer's Disease (Journal of Alzheimer's Disease, Volume 16, Number 4, April 2009 – Special Issue "Oxidative Stress, Reactive Metabolites, Inflammation, and RAGE – Building a Bridge from Alzheimer's Disease to Diabetes and Vice Versa") It is devoted to the problem of the relationship between the causes of Alzheimer's disease and type II diabetes.
Numerous epidemiological studies indicate the simultaneous spread of Alzheimer's disease and type II diabetes in the West and an increase in the impact of harmful environmental factors. The guest editors – Angelika Bierhaus and Peter P. Nawroth from Heidelberg University – gathered a group of outstanding researchers whose task was to establish a link between Alzheimer's disease and type II diabetes based on scientific reviews, clinical data, data obtained from animal models, pathophysiological studies and biochemical analysis.
In the introduction, the editors note a number of pathologies characterized by researchers as common to Alzheimer's disease and diabetes. Among them are impaired (decreased) glucose metabolism, changes in signaling pathways involving insulin, mitochondrial disorders, oxidative stress and inflammation.
Daniel Kopf and Lutz Frölich systematized data from fourteen studies on the risk of developing Alzheimer's disease in patients with type II diabetes. The analyzed data allow us to assess such a development of events as statistically reliable with a probability of 1:4.
Pablo Toro, Peter Schönknecht, and Johannes Schröder were based on survey data from more than 200 patients born between 1930 and 1932. Among them, along with a slight impairment of the ability to recognize and Alzheimer's disease, there is a tendency to increase the number of cases of type II diabetes.
Jose A. Luchsinger and Deborah R. Gustafson presented an extremely comprehensive review of the epidemiological signs linking obesity with type II diabetes and Alzheimer's disease. The mechanism of this relationship may be based on an increase in the level of insulin and glycosylation byproducts (including reactive oxygen species and beta-amyloid protein), a deterioration in blood supply to the brain, as well as increased exposure to adipocytokines (proteins that transmit signals from a fat cell capable of penetrating the blood-brain barrier) as a result of obesity.
Ceramides are lipid molecules that are both toxic to neurons and provide immunity to insulin. Ming Tong and Suzanne M. de la Monte have compiled a report on the role of ceramides as mediators based on their own data obtained in vitro on a cellular model. Exposure to two different ceramides reduces the level of metabolism, cell viability and interferes with the signaling mechanisms of insulin and insulin-like growth factors and leads to an increase in the level of beta-amyloid protein and its precursor, phosphorylated tau proteins, which is characteristic of the development of Alzheimer's disease. At the same time, inactivated ceramides do not have such an effect on the listed factors.
Following this line of research, a group of scientists, including Thune and de la Monte, studied two groups of mice – control and kept on a high-fat diet. It was found that the result of such a diet is minor neurodegenerative disorders and resistance of brain cells to insulin. In addition, in experimental animals, compared with control animals, the level of ceramides, which contribute to the development of obesity, diabetes and non-alcoholic cirrhosis of the liver, is increased.
A group of 11 researchers worked to describe the possible role of leptin – a protein hormone involved in the regulation of body weight – in reducing the impact of Alzheimer's disease. They suggest that a deficiency of leptin or a violation of its functions can lead to disorders of the central nervous system preceding Alzheimer's disease.
Three of the presented articles highlight the role of oxidative stress in the development of Alzheimer's disease. Paula I. Moreira, Ana I. Duarte, Maria S. Santos, Cristina Rego and Catarina R. Oliveira paid attention to the molecular processes underlying Alzheimer's disease, including deterioration of glucose metabolism, disruption of mitochondria and insulin signaling pathways, oxidative stress. Prakash Reddy, Xiongwei Zhu, George Perry and Mark A. Smith discussed the leading role of oxidative stress in the development of type II diabetes, Alzheimer's disease and other neurodegenerative diseases. Excessive levels of end products of glycosylation and lipid peroxidation are characteristic of type II diabetes and Alzheimer's disease and serve as a marker of the degree of disease development in the case of both diseases. Sayyad Muhammad, Angelika Bierhaus and Markus Schwaninger reviewed data on the role of reactive oxygen species in vascular dysfunction in type II diabetes and cerebral ischemia and the relationship of these disorders with Alzheimer's disease.
Allan Jones, Philipp Kulozik, Anke Ostertag and Stephan Herzig assessed the general metabolic and inflammatory processes that occur in both type II diabetes and Alzheimer's disease. In particular, they emphasize the role of critical control points of the cell cycle in cellular metabolism, insulin sensitivity and inflammation. The transcription regulators involved in this case, according to the authors, are a target for therapeutic effects in the combined therapy of type II diabetes and Alzheimer's disease. Another group of scientists investigated the degree of co-involvement of inflammation and transcription factor NF-kB in the development of these diseases, the activity of which varies rapidly depending on a number of intracellular stimuli. Clement T. Loy and Stephen M. Twigg Twigg) discussed how excess glycolysis products and impaired regulation of growth factors are interrelated with these diseases.
The receptors of glycosylation products constitute a superfamily of molecules, which includes the beta-amyloid protein receptor. An increase in proteins of this family is observed in parts of the brain affected by Alzheimer's disease, and the beta-amyloid receptor in vitro causes stress with the formation of reactive oxygen species and activates signaling pathways through the feedback mechanism. Presumably, these receptors may become another target in the treatment of Alzheimer's disease.
Masayoshi Takeuchi and Sho-ichi Yamagishi have contributed to the study of toxic glycosylation products that lead to oxidative stress in many cell types. Akihiko Taguchi described the effect of chronic inflammation caused by overexpression of glycosylation product receptors on the development of positive feedback between epithelial cells and neurons and its role in neurodegradation. Elzbieta Kojro and Rolf Postina investigated the effect of insulin on the receptors of glycosylation products and proteolysis of A4-peptide, a precursor of beta-amyloid (the product of its improper proteolysis is a toxic beta-amyloid protein), as well as how proteolysis of the receptors of glycosylation products can prevent the penetration of beta-amyloid through the blood-brain barrier.
Free iron ions can also contribute to the formation of reactive oxygen species. Sandro Altamura and Martina U. Muckenthaler have prepared a review of experimental evidence for the involvement of iron in the development of Alzheimer's disease and type II diabetes. They suggest that iron plays a role in the development of atherosclerosis.
Michael Morcos and Harold Hutter examined a classic model for studying the aging process – the nematode Caenorhabditis elegans (C.elegans), which has a lot in common with humans at the molecular level. C.elegans has a well-defined and sufficiently developed nervous system, as well as a number of genes homologous to those involved in the development of the disease Alzheimer's human genes, such as beta-amyloid protein precursor, transmembrane proteins of the presenelin family and tau proteins.
As a result of the aging of the population, the epidemic of obesity and other "diseases of civilization", the number of patients with diabetes mellitus and Alzheimer's disease in the world is increasing every year and, unfortunately, there is no reduction in the rate of morbidity growth. However, the relationship between the mechanisms of development of these diseases is also a unique opportunity for their prevention and treatment.
Polina Babich
Portal "Eternal youth" http://vechnayamolodost.ru Based on ScienceDaily: Connections Between Diabetes And Alzheimer's Disease Explored15.05.2009